ABSTRACT Exposure to cockroach allergen can lead to allergic sensitization and an increased risk of allergic asthma. However, the underlying molecular mechanisms are currently not well-established. Our long-term goals are to elucidate the fundamental underlying mechanisms and identify novel therapeutic targets for allergic asthma. During the period of the NIH-funded project (RO1 ES021739), our group has made significant contributions to unraveling an important link between cockroach antigen and development of allergic asthma. Specifically, our profiling of N-linked glycans from cockroach allergen identified several major glycans with high affinity to mannose receptor, MRC1/CD206. Furthermore, we have identified a critical but previously unrecognized role of MRC1 in allergen clearance as a natural defense mechanism and in limiting the progression and severity of cockroach allergen-induced allergic inflammation in a mouse model of asthma. This occurs through alterations in macrophage clearance of the inhaled cockroach allergens and balance of M1/M2 macrophage polarization. This was at first perplexing because MRC1 lacks any known signaling motif, therefore, the signaling cascades of MRC1 in allergen-induced airway inflammation and macrophage polarization remain obscure. Our breakthrough for a deeper understanding of the MRC1 signaling pathway came with the recognition that a key regulatory miR-511-3p, encoded by both mouse and human MRC1 gene, is transcriptionally co-regulated with MRC1 in macrophages. These exciting findings lead us to propose a novel hypothesis that the impressive protective effect of MRC1 on allergen-induced airway inflammation and macrophage polarization is not due to the receptor per se, but to the regulatory influences of miR-511-3p. This hypothesis is further buttressed by our important recent findings: first, the levels of miR-511-3p were lower in the plasma of asthmatics compared to controls; and second, treatment of Mrc1-/- mice with adeno-associated virus vector (AAV-miR-511-3p) attenuated the allergen-induced airway inflammation in Mrc1-/- mice. These exciting data set the stage to critically evaluate the functional significance of miR-511-3p as a potential therapeutic target for allergic asthma. Three independent yet related specific aims are proposed. Aim 1 proposes studies to determine whether miR-511-3p expression is down-regulated not only in plasma, but also in sputum, macrophages from sputum, and BALFs of patients with allergic asthma. Aim 2 proposes experiments to define whether miR-511-3p plays a role in allergic asthma using miR-511-3p knockout mice or mice with miR-511-3p over-expression. Aim 3 proposes studies to identify miR- 511-3p targets by integrating gene profiling, in silico analysis, and our unique affinity-based transcriptomic approach for miR-511-3p binding partner mRNAs/long non-coding RNAs. Taken together, the study is significant since it provides a conceptual framework linking environmental allergens, MRC1, and miR-511-3p to key features of asthma. The approach is innovative because of integrating studies on human subjects, novel in vivo models, and specific tools. Ultimately, these studies may allow for the development of new therapeutic targets for asthma.